N-(biphenylmethyl)-3-hydroxyglutaramic acid and derivatives as hypocholesterolemic agents

ABSTRACT

Variously substituted 4-(biphen-2-ylmethylcarbamoyl)-3-hydroxybutyric acids and esters, also named as N-(biphen-2-yl)-3-hydroxyglutaramic acid derivatives, are blood cholesterol lowering agents and so are useful in the prevention and treatment of cardiovascular diseases such as atherosclerosis.

BACKGROUND OF THE INVENTION

Variously substituted N-(biphen-2-ylmethyl)-3-hydroxyglutaramic acid andderivatives, as defined by the formula (I) below (alternatively named as4-(biphen-2-ylmethylcarbamoyl)-3-hydroxybutyric acid derivatives)possess hypocholesterolemic (blood cholesterol lowering) activity and soare useful in the prevention and treatment of certain cardiovasculardiseases such as atherosclerosis.

Previously reported as hypocholesterolemic compounds have been variouslysubstituted 6-phenyl-, 6-(2-phenethyl)-, 6-(3-phenylpropyl)- and6-(2-styryl)-4-hydroxy-6-hexanolides including, in particular, ##STR1##and the corresponding ring opened 3,5-dihydroxyomega-substituted-(hexan-, heptan-, octan- and 6-hepten-)oic acids [Willard et al., U.S.Pat. Nos. 4,375,475 and 4,459,422; see also Mitsui et al., U.S. Pat. No.4,198,425; Stokker et al., J. Med. Chem., vol. 28, pp. 347-358 (1985)].

SUMMARY OF THE INVENTION

The present invention is directed to hypocholesterolemic compoundshaving the formula ##STR2## wherein

R is hydrogen, (C₁ -C₃)alkyl, phenyl, benzyl or a conventional radicalforming an ester group which is hydrolyzable under physiologicalconditions;

X is F, Cl, Br, I, (C₁ -C₃)alkyl, CF₃, benzyl, (C₁ -C₃)alkoxy, (C₂-C₄)alkanoyloxy or (C₂ -C₄)alkoxycarbonyl; and

X¹, X² and X³ are each independently hydrogen, F, Cl, Br, I, (C₁-C₃)alkyl, CF₃, benzyl, (C₁ -C₃)alkoxy, (C₂ -C₄)alkanoyloxy or (C₂-C₄)alkoxycarbonyl; and the pharmaceutically-acceptable cationic saltsthereof when R is hydrogen.

The depiction of the substituents X, X¹, X² and X³ in the compound ofthe formula (I) is not intended to limit the substituents on each ringto two. Rather, while the substituent X is specifically substituted atthe 3-position, it is intended that each of the remaining threesubstituents, if present, can be substituted at any open position oneither phenyl ring. For example, all three of X¹, X² and X³ areoptionally substituted on one or the other of the phenyl rings.

The preferred compound, because of its ease of preparation and level ofhypocholesterolemic activity, has R as hydrogen, and X, X¹ and X² as3,3',5-trimethyl and X⁴ as 4'-fluoro.

Pharmaceutically-acceptable cationic salts include, but are not limitedto, those of sodium, potassium, calcium, N,N'-dibenzylethylenediamine,N-methylglucamine (meglumine) and diethanolamine. The preferred cationicsalts are those of potassium and sodium.

The reference to esters which are hydrolyzable under physiologicalconditions refers to those esters frequently referred to as "pro-drugs".Such esters are now as well-known and common in the medicinal art aspharmaceutically-acceptable salts. Such esters are generally used toenhance oral absorption, but in any event are readily hydrolyzed in vivoto the parent acid. The more preferred ester forming radicals are thosewherein R is:

furan-5(1H)-on-1-yl;

isobenzofuran-3(1H)-on-1-yl;

3,4-dihydrofuran-5(1 H)-on-1-yl;

--CHR¹ OCOR² ; or

--CHR¹ OCOOR² ;

wherein R¹ is hydrogen or methyl; and R² is (C₁ -C₆)alkyl. The mostpreferred radicals are pivaloyloxymethyl and 1-(ethoxycarbonyloxy)ethyl.

The present invention also encompasses pharmaceutical compositions forthe treatment or prevention of atherosclerosis in a mammal whichcomprises a blood cholesterol lowering effective amount of a compound ofthe formula (I); and method of treating or preventing atherosclerosis ina mammal which comprises administering a blood cholesterol loweringeffective amount of a compound of the formula (I) to said mammal.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is readily carried out. Thus, the hydroxyprotected anhydride of 3-hydroxyglutaric anhydride (alternatively named3-hydroxypentanedioic anhydride), e.g.,3-(t-butyldimethylsilyloxy)glutaric anhydride, is reacted with adiphen-2-ylamine of the formula ##STR3## wherein X, X¹, X² and X³ are asdefined above, in the conventional manner long used to prepare halfamides from amines and cyclic anhydrides. For example, see and Boyd,"Organic Chemistry", 3rd Ed., Allyn and Bacon, Inc., Boston, 1973, pp.668-670, and the examples below. To assure maintenance of the hydroxyprotecting group during the anhydride-amine reaction, basic conditionsare generally maintained by using either an excess of the amine (i.e. atleast 2 molar equivalents of amine relative to anhydride) or an excessof a tertiary amine (e.g., triethylamine, 4-dimethylaminopyridine; atleast 1 molar equivalent thereof when substantially 1 molar equivalentof the amine reactant is employed). At the same time, reaction rate isgenerally enhanced by the presence of the excess amine reactant ortertiary amine. The reaction is generally carried out in areaction-inert solvent, such as methylene chloride. As used herein, theterm reaction-inert solvent refers to a solvent which does not interactwith reactants, intermediates or products in a manner which adverselyaffects the yield of the desired product. Temperature is not critical,e.g., 0°-50° C., conveniently ambient temperatures, being generallysatisfactory. If desired, in order to avoid undue exotherms, thereaction can be initiated at a lower temperature, e.g. 0° C. to -70° C.,then brought to a higher temperature for completion of the reaction

If the protecting group (e.g., t-butyldimethylsilyl) is not removed byacid hydrolysis during isolation, it can be removed in a separate step,in either case, involving conventional acid cleavage (e.g., with HF inCH₃ CN as exemplified below) or conventional acid catalyzed hydrolysisor solvolysis, yielding an acid compound of the formula (I) wherein R isH.

By conventional modification of the isolation procedure, the compoundsof the formula (I) wherein R is H are alternatively isolated in the formof a pharmaceutically-acceptable cationic salt, as defined above. Suchsalts are also readily prepared from the isolated acid forms by standardmethods. For example, an equivalent of the corresponding cationichydroxide, carbonate or bicarbonate, or of an amine, is combined withthe carboxylic acid in an organic or aqueous solvent. The salt isisolated by concentration and/or the addition of a non-solvent.

The (C₁ -C³)alkyl, phenyl and benzyl esters encompassed by the formula(I) are also readily prepared from the acid forms by conventionalmethods. In those methods which involve reaction of an activated form ofacid with a (C₁ -C₃)alkanol, phenol or benzyl alcohol, it is preferredto prepare the desired ester from an acid in which the 3-hydroxy groupis in protected form (e.g., as the t-butyldimethyl silyl etherderivative), so as to avoid potential dimerization/polymerization as aside reaction. Such a protecting group is removed by mild acidhydrolysis, or treatment with fluoride ion, during isolation of theester, or as a final step, care being taken to avoid acid conditionssufficiently vigorous to hydrolyze the desired ester group.

Mixed anhydrides are well-suited as the activated acid form in thepreparation of said alkyl, phenyl and benzyl esters. Generally, theacids are first converted in situ to a tertiary amine salt in thepresence of a 1 to 1.1 molar excess of the amine. A variety of tertiaryamines are suitable for this purpose. Exemplary are triethylamine,N-methyl-piperidine, N-methylmorpholine, dimethylaniline or quinoline.Suitable inert solvents are methylene chloride, chloroform,dimethylformamide, and dimethyl-acetamide. It is preferrable that theacid be completely dissolved by the excess of tertiary amine, which mayrequire a stirring period, together with gentle warming, if necessary.The solution of amine salt is then reacted with an equivalent of alkyl(e.g. ethyl), benzyl, or phenyl chloroformate, at a temperature in therange of -40° to 25° C., preferably in the range -10° to 10° C., to forma mixed anhydride in solution. Without isolation, the mixed anhydride isreacted directly with the appropriate alcohol or phenol to yield thedesired ester. The reaction is usually initiated at a cool temperature(such as -40° to 15° C.), but allowed to warm to higher temperature(such as 15° to 40° C.) to complete the reaction.

The above alkyl and benzyl esters are alternatively prepared, and theesters wherein R is a conventional radical forming an ester which ishydrolyzable under physiological conditions are generally prepared, byreaction of a salt of the acid (I, R=H; preferably thetetrabutylammonium salt) with an appropriate compound containing adisplaceable halide (iodide, bromide or chloride; generally preferred,where available, in that order), or another group suitable fornuclophilic displacement. Exemplary are CH₃ OSO₂ CH₃, C₂ H₅ Br, CH₃ CH₂CH₂ I, ICHR¹ OCOR², ICHR¹ OCOOR², ##STR4## The required salt can be inisolated form, or more conveniently, formed in situ from the acid by useof at least one equivalent of a base. The reaction is carried out in areaction-inert solvent, preferably one which is essentially anhydrous. Aparticularly convenient reaction system employs excess potassiumcarbonate as base in acetone as solvent. When the halide is chloro orbromo, up to three or more equivalents of anhydrous sodium iodide isadded, if desired, to enhance the rate of reaction. An excess of thehalide reagent is not critical to the reaction, but such an excess willgenerally be used in order to force the reaction to completion in ashorter period of time. The rate of reaction will also depend greatly onthe halide (e.g., I>Br>Cl) and on the nature of the radical group R(e.g., more branched ICHCH₃ OCOCH₃ will react more slowly than ICH₂OCOCH₃). The reaction temperature is not critical, a temperature in therange of 0°-100° C. being generally satisfactory.

The required hydroxy protected anhydride is available according to themethod of Rosen et al., J. Org. Chem., vol. 49, pp. 3657-3659 (1984).

The required amines of the formula (II) are available by conventionalmethods from the corresponding aldehyde (e.g., by reductive alkylation,or by hydride reduction of the corresponding oxime, as exemplified inPreparations below). The required aldehydes are prepared according toprocedures described by Willard et al., loc. cit. and Stokker et al.,loc. cit.

The biological procedures for evaluating these compounds were asfollows: Rat liver microsomal, HMG-CoA(3-hydroxy-3-methylglutaryl-coenzyme A) reductase was isolated,solubilized and purified through the heat fractionation methods ofRogers et al., Analytical Biochemistry, vol. 101, pp. 107-111 (1980).HMG-CoA reductase activity was measured according to the procedure ofHarwood et al., J. Lipid. Res., vol. 25, pp. 967-978 (1984). Inhibitionof rat cholesterol biosynthesis was measured using ¹⁴ C-acetateaccording to the procedure of Endo et al., Eur. J. Biochem., vol. 77,pp. 31-36 (1977).

For use in the treatment or prevention of atherosclerosis in a mammal,including man, a compound of the formula (I) is administered in a bloodcholesterol lowering (or a low blood cholesterol maintaining) amount ofabout 1-50 mg/kg/day, in single or divided daily doses. In particularcases, dosages outside that range are prescribed at the discretion ofthe attending physician. The preferred route of administration isgenerally oral, but parenteral administration (e.g. intramuscular,intravenous, intradermal) will be preferred in special cases, e.g.,where oral absorption is impaired as by disease, or the patient isunable to swallow.

The compounds of the present invention are generally administered in theform of pharmaceutical compositions comprising at least one of thecompounds of the formula (I), together with a pharmaceuticallyacceptable vehicle or diluent. Such compositions are generallyformulated in a conventional manner utilizing solid or liquid vehiclesor diluents as appropriate to the mode of desired administration: fororal administration, in the form of tablets, hard or soft gelatincapsules, suspensions, granules, powders and the like; and, forparenteral administration, in the form of injectable solutions orsuspensions, and the like.

The present invention is illustrated by the following examples, but isnot limited to the details thereof.

EXAMPLE 14-[(4'-Fluoro-3,3',5-trimethylbiphen-2-yl)-methylcarbamoyl]-3-[(t-butyldimethylsilyl)oxy]-butyricAcid

To a -60° C. solution of 2-aminomethyl-4-fluoro-3,3'5-trimethylbiphenyl(2.30 g, 9.45 mmol), 4-dimethylaminopyridine (0.175 g, 1.43 mmol) andtriethylamine (0.508 g, 5.00 mmol) in anhydrous methylene chloride (22ml) was added 3-(t-butyldimethylsilyoxy) glutaric anhydride (2.43 g,9.93 mmol). After stirring at -60° C. for 1 hour, the reaction waswarmed to -20° C. for 1 hour, and then to 0° C. for an additional 16hours. The reaction mixture was diluted with ether (50 ml), then washedwith 1M phosphoric acid (22 ml) and saturated aqueous sodium bicarbonate(2×22 ml). The combined aqueous phases were acidified with phosphoricacid (65 ml) to a pH of 4, then extracted with ether (2×22 ml). Thecombined organic phases were dried with magnesium sulfate, filtered andconcentrated in vacuo to give 4.783 g (quantitative yield) of crudeproduct. A portion of this material (1.50 g) was purified by flashchromatography (1:1 methanol:ethyl acetate) to give 1.472 g of purifiedtitle product.

High resolution mass spectra: m/e found 487.2610, calc. for C₂₇ H₃₈ FNO₄Si 487.2554. ¹ H-NMR (CDCl₃), delta 10.20 (br, s, 1 H); 7.06-6.94 (m, 4H); 6.84 (s, 1 H); 6.37 (t, 5 Hz, 1 H); 4.41 (pentet, 6 Hz, 1 H); 4.27(d, 5 Hz, 2 H); 2.51 (d, 6 Hz, 4 H); 2.33 (s, 3 H); 2.28 (s, 3 H); 2.27(d, 2 Hz, 3 H); 0.66 (s, 9H); 0.01 (s, 3 H); -0.03 (s, 3 H). ¹³ C-NMR(CDCl₃), delta: 174.2, 170.7, 162.3, 159.0. 142.5, 137.8, 137.4, 137.0,136.9, 132.0, 131.9, 130.8, 129.5, 128.8, 127.8, 127.7, 124.7, 124.5,114.9, 114.6, 66.6, 42.8, 38.8, 29.7, 25.4, 20.9, 19.6, 17.6, 14.6, 14.6(fluorine not decoupled). IR (CHCl₃) cm⁻¹ : 3520, 3450, 3370, 2980,2950, 2930, 2860, 1715, 1660, 1620, 1495, 1465.

EXAMPLE 24-[(4'-Fluoro-3,3',5-trimethylbiphen-2-yl)-methylcarbamoyl]-3-hydroxybutyricAcid

A solution of 20% hydrofluoric acid in acetonitrile (54 ml) was added toa suspension of the title product of the preceding Example (2.69 g, 5.52mmol) in acetonitrile (215 ml). The resulting mixture was stirred for 20hours. The reaction mixture was then neutralized by adding solid sodiumbicarbonate with vigorous stirring. The resulting suspension wasfiltered through a pad of solid sodium bicarbonate and concentrated invacuo to give 3.153 g of a yellow solid. This solid was dissolved inwater (80 ml). The resulting mixture was basified with saturated aqueoussodium bicarbonate (10 ml) to a pH of 10 and extracted with ethylacetate (3×20 ml). The aqueous phase was then acidified with 1Nhydrochloric acid 915 ml) to a pH of 2 and extracted with ethyl acetate(2×20 ml). The combined extracts were dried over magnesium sulfate,filtered and concentrated to give 0.294 g (14% yield) of present titleproduct; mp 152°-154° C.

High resolution mass spectra: m/e found 373.1681, calc. for C₂₁ H₂₄ FNO₄373.1689. ¹ H-NMR (CDCl₃), delta: 7.13-6.93 (m, 4 H); 6.89 (s, 1 H);6.50 (t, 5 Hz, 1 H), 4.39-4.26 (m, 1 H); 4.22 (d, 5 Hz, 2 H); 2.48 (d, 6Hz, 2 H); 2.41-2.21 (m, 11 H); 2.08 (s, 1H). ¹³ C-NMR (CDCl₃), delta:173.5, 170.9, 142.6, 138.1, 136.8, 132.0, 131.9, 130.4, 130.0 128.5,127.8, 127.7, 124.0, 114.6, 114.2, 41.7, 41.2, 38.7, 20.8, 19.4. IR(CHCl₃) cm⁻¹ : 3300, 2960, 2930, 1710, 1630, 1540, 1505, 1475.

EXAMPLE 3

By the methods of Examples 1-2, the aminomethyl derivatives ofPreparation 3 are converted to the corresponding4-[(substituted-biphen-2-yl)methyl carbamoyl]-3-hydroxybutyric acids.

EXAMPLE 4 Ethyl4-[(4'-Fluoro-3,3',5-trimethyl-biphen-2-yl)methylcarbamoyl]-3-[(t-butyldimethylsilyl)oxy]butyrate

Title product of Example 1 (1.95 g, 4 mmol) is dissolved in 40 ml ofmethylene chloride and triethylamine (1.12 ml, 8 mmol), with warming to40° C., if necessary, and then cooled to 0°-5° C. Ethyl chloroformate(0.39 ml, 4.1 mmol) diluted with 5 ml of CH₂ Cl₂ is added at a ratewhich maintains a temperature of 0°-5° C. and the mixture stirred for 1hour after addition is complete. Finally, anhydrous ethanol (0.25 ml,4.2 mmol) diluted with 5 ml of CH₂ Cl₂ is added over 5 minutes, and themixture warmed to 20°-25° C. and stirred overnight. The reaction mixtureis washed in sequence with 25 ml 1M phosphoric acid, 25 ml saturatedNaHCO₃ and 25 ml water, dried (MgSO₄) and stripped in vacuo to yieldtitle product.

Substituting a molar equivalent of methanol, isopropanol, phenol orbenzyl alcohol in this process produces the corresponding methyl,isopropyl, phenyl or benzyl ester, respectively.

EXAMPLE 5 Ethyl4-[(4'-Fluoro-3,3',5-trimethylbiphen-2-yl)methylcarbamoyl]-3-hydroxybutyrate

The product of the preceding example is deprotected with HF/CH₃ CNaccording to the method of Example 2. To purify, the crude product istaken into ethyl acetate, extracted with 1M phosphoric acid, saturatedNaHCO₃ and water, dried and restripped.

By the same method the other 3-hydroxy protected esters of the precedingExample are converted to the corresponding methyl, isopropyl, phenyl andbenzyl esters.

EXAMPLE 6 Pivaloyloxymethyl4-[(4'-Fluoro-3,3',5-trimethylbiphen-2-yl)methylcarbamoyl]-3-hydroxybutyrate

Tetrabutylammonium hydrogen sulfate (0.374 g, 1.1 mmol) is dissolved in2.5 ml H₂ O. NaHCO₃ (92 mg, 1.1 mmol) is added portionwise at a ratewhich controls foaming. Finally, title product of Example 2 (0.41 g, 1.1mmol) is added. After about 30 minutes of stirring, the solution isextracted 4×5 ml CHCl₃ and the combined extracts dried and stripped toyield intermediate tetrabutylammonium salt. Under nitrogen, the latteris dissolved in 2 ml acetone and chloromethyl pivalate (0.216 ml, 1.1mmol) is added. After 24 hours, the acetone is stripped and the residuedissolved in 5 ml ethyl acetate, washed 3×5 ml water and 1×5 ml brine,dried and restripped to yield title product. The reaction rate isenhanced, and the reaction time shortened by the addition of NaI(0.15-0.30 g, 1-2 mmol) to the acetone reaction mixture and/or by usingelevated temperatures (e.g., the reflux temperature of acetone).

The corresponding methyl, hexanoyloxymethyl, 1-(isobutyryloxy)ethyl,1-(methoxycarbonyloxy)ethyl, isobenzofuran-3(1H)-on-1-yl (3-phthalidyl)and gamma-butyrolacton-4-yl (3,4-dihydrofuran-5(1H)-on-1-yl) esters areprepared by the same method, substituting a molar equivalent of methyliodide, chloromethyl hexanoate, 1-chloroethyl isobutyrate,3-bromophthalide, and 4-bromo-gamma-butyrolactone, respectively, forchloromethyl pivalate.

EXAMPLE 7 1-(Ethoxycarbonyloxy)ethyl4-[(4'-Fluoro-3,3',5-trimethylbiphen-2-yl)methylcarbamoyl]-3-hydroxybutyrate

The title product of Example 2 (4.1 g, 0.011 mol), K₂ CO₃ (3.0, 0.022mol), 1-chloroethyl ethyl carbonate (5.0, 0.033 mol) and NaI (1.65 g,0.011 mol) are combined in 60 ml of acetone and heated at refluxovernight. The reaction mixture is stripped in vacuo to a volume of 10ml and then diluted with 100 ml each of H₂ O and CH₂ Cl₂. The organiclayer is separated, washed with 100 ml H₂ O, dried (Na₂ SO₄) andstripped in vacuo to yield title product.

By the same method 5-bromofuran-2(5H)-one and chloromethyl pentanoateare converted, respectively, to the corresponding furan-5(1H)-on-1-yland pentanoylmethyl esters.

PREPARATION 1 2-Methoxyiminomethyl-4'-fluoro-3,3',5-trimethylbiphenyl

Methoxylamine hydrochloride (0.190 g, 227 mmol) was added to a solutionof 4'-fluoro-3,3',5-trimethylbiphenyl-2-carbaldehyde (0.500 g, 2.06mmol), in pyridine (5.0 ml). The reaction mixture was stirred for 17hours and then concentrated in vacuo to give 1.068 g of a yellow oil.Water (1.0 ml) was added and the resulting suspension was extracted withether (3×1.0 ml). The combined extracts were dried over magnesiumsulfate, filtered and concentrated in vacuo to give 0.588 g (99% yield)of title product.

High resolution mass spectra m/e found 271.1329, calc. for C₁₇ H₁₈ FNO271.1372. ¹ H-NMR (CDCl₃), delta: 7.98 (s, 1 H); 7.15-7.01 (m, 4 H);6.96 (s, 1 H); 3.92 (s, 3 H); 2.58 (s, 3 H); 2.38 (s, 3 H); 2.34 (s, 3H). ¹³ C-NMR (CDCl₃), delta: 162.4, 149.0, 142.4, 138.4, 137.8, 136.5,136.4, 132.8, 132.7, 131.3, 128.7, 128.6, 128.5, 125.7, 124.6, 124.4,114.7, 114.4, 61.8, 22.5, 21.1, 14.6, 14.5. IR (CHCl₃) cm⁻¹ : 2980,2950, d 2920, 2830, 1615, 1510, 1470, 1450.

PREPARATION 2 2-Aminomethyl-4'-fluoro-3,3',5-trimethylbiphenyl

A solution of the title product of the preceding Preparation (3.29 g,12.1 mmol) in anhydrous tetrahydrofuran (25 ml) was added dropwise withstirring to a suspension of lithium aluminum hydride (0.619 g, 16.3mmole) in (50 ml). The resulting mixture was refluxed for 2 hours, thenallowed to cool room temperature. The reaction was quenched bysuccessive addition of water (1.0 ml), 15% aqueous sodium hydroxide (1.0ml) and water (3.0 ml). The precipitate that formed was collected byfiltration and washed with ether (50 ml). The combined filtrates wereconcentrated in vacuo to give 2.889 g of a yellow oil. Purification byflash chromatography (toluene) gave 2.41 g (82% yield) of title product.

High resolution mass spectra: m/e found 243.1425 calc. for C₁₆ H₁₈ FN243.1424. ¹ H-NMR (CDCl₃), delta: 7.17-6.96 (m, 4 H); 6.87 (s, 1 H);3.71 (s, 2 H); 2.45 (s, 3 H); 2.33 (s, 3 H); 2.31 (s, 3 H); 1.17 (s, 2H). ¹³ C-NMR (CDCl₃), delta: 162.8, 158.9, 141.5, 137.8, 137.7, 136.6.136.1, 136.0, 132.2, 132.1, 130.8, 128.8, 127.9, 127.8, 124.5, 124.3,114.7, 114.4, 40.3, 20.9, 19.5, 14.7, 14.6. IR (CHCl₃) cm⁻ : 3360, 2940,2910, 2870, 1595, 1490, 1465.

PREPARATION 3

By the methods of Preparations 1 and 2, the following additional2-(aminomethyl)biphenyls are prepared from the appropriately substitutedbiphenyl-2-carbaldehyde:

2-(Aminomethyl)-3,5-dichlorobiphenyl;

2-(Aminomethyl)-3,4',5-trichlorobiphenyl;

2-(Aminomethyl)-3,5-dichloro-3'-methylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-3,5'-dimethylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-4'-fluorobiphenyl;

2-(Aminomethyl)-3,5-dichloro-4'-fluoro-2'-methylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-3'-ethylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-3'-methylbiphenyl;

2-(Aminomethyl)-3,3',5,5'-tetrachlorobiphenyl;

2-(Aminomethyl)-3,3',4,5-tetrachlorobiphenyl;

2-(Aminomethyl)-3,5-dichloro-2'-methylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-3'-methoxybiphenyl;

2-(Aminomethyl)-3,5-dichloro-4'-methoxybiphenyl;

2-(Aminomethyl)-3,5-dichloro-3'-fluorobiphenyl;

2-(Aminomethyl)-5-chloro-4'-fluoro-3,3'-dimethylbiphenyl;

2-(Aminomethyl)-3',4'-dichloro-3,5-dimethylbiphenyl;

2-(Aminomethyl)-3,3',5,5'-tetramethylbiphenyl;

2-(Aminomethyl)-4'-fluoro-3,5-dimethylbiphenyl;

2-(Aminomethyl)-3',4'-dichloro-3,6-dimethylbiphenyl;

2-(Aminomethyl)-3-chloro-4'-fluoro-3'-methylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-4'-methylbiphenyl;

2-(Aminomethyl)-3,5-dichloro-4'-methoxybiphenyl; and

2-(Aminomethyl)-3,5-dichloro-3'-fluorobiphenyl.

I claim:
 1. A compound having the formula ##STR5## wherein R ishydrogen, (C₁ -C₃)alkyl, phenyl, benzyl or a conventional radicalforming an ester group which is hydrolyzable under physiologicalconditions;X is F, Cl, Br, I, (C₁ -C₃)alkyl, CF₃, benzyl, (C₁-C₃)alkoxy, (C₂ -C₄)alkanoyloxy or (C₂ -C₄)alkoxycarbonyl; and X¹, X²and X³ are each independently hydrogen, F, Cl, Br, I, (C₁ -C₃)alkyl,CF₃, benzyl, (C₁ -C₃)alkoxy, (C₂ -C₄)alkanoyloxy or (C₂-C₄)alkoxycarbonyl; or a pharmaceutically acceptable cationic saltthereof when R is hydrogen.
 2. A compound of claim 1 wherein R is aradical selected from the group consisting of:furan-5(1H)-on-1-yl;isobenzofuran-3(1H)-on-1-yl; 3,4-dihydrofuran-5(1H)-on-1-yl; --CHR¹OCOR², and --CHR¹ OCOOR² ;wherein R¹ is hydrogen or methyl; and R² is(C₁ -C₆)alkyl.
 3. A compound of claim 1 wherein R is hydrogen, (C₁-C₃)alkyl, phenyl or benzyl.
 4. A compound of claim 3 wherein R ishydrogen.
 5. The compound of claim 4 wherein X is 3-methyl, X¹ is5-methyl, X² is 3'-methyl and X³ is 4'-fluoro.
 6. A pharmaceuticalcomposition for the treatment or prevention of atherosclerosis in amammal which comprises a blood cholesterol lowering effective amount ofa compound of claim
 1. 7. A pharmaceutical composition for the treatmentor prevention of atherosclerosis in a mammal which comprises a bloodcholesterol lowering effective amount of a compound of claim
 4. 8. Apharmaceutical composition for the treatment or prevention ofatherosclerosis in a mammal which comprises a blood cholesterol loweringeffective amount of the compound of claim
 5. 9. A method of treating orpreventing atherosclerosis in a mammal which comprises administering ablood cholesterol lowering effective amount of a compound of claim 1 tosaid mammal.
 10. A method of treating or preventing atherosclerosis in amammal which comprises administering a blood cholesterol loweringeffective amount of a compound of claim 4 to said mammal.
 11. A methodof treating or preventing atherosclerosis in a mammal which comprisesadministering a blood cholesterol lowering effective amount of thecompound of claim 5 to said mammal.